Efforts to develop effective measures for the treatment of stroke have generally been based on the implicit assumption that one, or at the most several, factors control the progressive brain injury that occurs during the early hours of focal brain ischemia. Postischemic progression of brain damage appears to be extremely multifactorial. There is a finite probability that the assumption underlying most therapeutic stroke trials that seek to identify a dominant or controlling factor that determines postischemic progression of brain damage is incompatible with the fundamental nature of the problem. Postischemic progression of brain damage may be the result of a constellation of minor causes and the quest for a dominant or controlling cause would then be ultimately futile. Unconventional approaches may be required to arrest cellular destruction in brain ischemia. This project continues to investigate mammalian hibernation, a state of natural tolerance to severely reduced blood flow and oxygen delivery. Efforts to isolate and identify the factor or factors that regulate the controlled metabolic depression and tolerance of profound brain ischemia that forms the essence of natural hibernation are in progress. In hippocampal slices, hibernation confers robust resistance to hypoxia and glucose deprivation as compared to slices from non-hibernating ground squirrels and rats at 37 degrees C, 20 degrees C and 7 degrees C. This indicates that hibernation involves tolerance to an in vitro form of ischemic stress that is not strictly dependent on temperature. Protein synthesis in the hippocampal slices was found to be greatly depressed at the same incubation temperatures. The regulation of this depression in protein syntheses is being investigated.